The expression of neurotrophins and their receptors, the low-affinity nerve growth factor receptor (p75 LNGFR ) and the Trk receptors (TrkA , TrkB, and TrkC) , was investigated in human bone marrow from 16 weeks fetal age to adulthood. Using reverse transcription-polymerase chain reaction , all transcripts encoding for catalytic and truncated human TrkB or TrkC receptors were detected together with trkAI transcripts , whereas trkAII transcripts were found only in control nerve tissues. Transcripts for the homologue of the rat truncated TrkC(ic113) receptor were identified for the first time in human tissue. Stromal adventitial reticular cells were found immunoreactive for all neutrophin receptors. In contrast, hematopoietic cell types were not immunoreactive for p75 LNGFR Nerve growth factor (NGF) 1 is the prototype of a family of related neurotrophic factors known as neurotrophins (NT), which also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4, also called neurotrophin-5 or NT-5 in humans) (reviewed in Lindsay et al 2 ). NT are trophic factors for the growth, differentiation, and survival of specific subsets of neurons in the developing and mature nervous system. 2 NT can interact with two classes of receptors with distinct ligand affinity and specificity. The low-affinity nerve growth factor receptor, p75 LNGFR , binds all known NT. 3,4 Tyrosine kinase receptors of the Trk family are essential components of NT high-affinity binding sites that trigger neuronal survival, growth, and differentiation. 5 TrkA is the preferred receptor for NGF 6,7 but has a lower efficiency for NT-3 or NT-4/5. TrkB is bound by BDNF and NT-4 and, to a lesser extent, by 9 TrkC is characterized by a unique ligand, NT-3. 10 In some cell lines, TrkA is sufficient to form high-affinity binding sites through homodimerization, 7 whereas p75 LNGFR potentiates TrkA activation by NGF in the PC12 cell line. 11 Variants of tyrosine kinase receptors (TK ϩ ) with insertions in either the extracellular domain (ECD) or the tyrosine kinase domain have been identified for trkA 12,13 and trkC [13][14][15][16] in both human and rat.Truncated receptors lacking the kinase domain (TK Ϫ ) have been described for TrkB and TrkC but not for TrkA. [15][16][17][18] These receptors may function as dominant negative isoforms or immunoadhesins. 13,19,20 Both TK ϩ and TK Ϫ receptors have been detected in neurons while only truncated TrkB and TrkC isoforms have been detected primarily in nonneuronal cells. [15][16][17][18]21 The expression of functional NGF receptors has been detected in several bone marrow-derived cells such as monocytes, 22 mastocytes, 23,24 and B or T cell clones. [25][26][27][28] Among its pleiotropic effects, NGF induces platelet shape changes, 29 triggers monocyte cytotoxic activity, 22 and induces basophilic cell differentiation 30 -32 and mast cell development and degranulation. 24,33 However, NGF receptors have not been consistently detected on bone marrow cells. Although trkA and p75 L...

The monoclonality of the T cell receptor gamma-chain gene was analyzed by polymerase chain reaction in skin and blood specimens of 85 patients with cutaneous T cell lymphomas including 67 mycosis fungoides, seven Sézary syndromes, and 11 CD30- nonepidermotropic cutaneous T cell lymphomas. A cutaneous T cell clone was detected in 69% of mycosis fungoides and 100% of Sézary syndromes. This frequency varied according to the clinical stage: 57% in early stages (Ia-IIa) to 96% in advanced stages (IIb-IV, Sézary syndrome). A peripheral blood T cell clone was detected in 42% of early stages and in 74% of late stages but was identical to the cutaneous one in 15% and in 63%, respectively. A significant association between initial clinical stage and T cell monoclonality was observed. In nonepidermotropic cutaneous T cell lymphomas, T cell monoclonality was detected in 55% of skin and 36% of blood samples. Univariate and multivariate analyses showed that, besides the initial clinical stage, an identical cutaneous and blood T cell clone was an independent prognostic factor for disease progression of mycosis fungoides/Sézary syndrome (hazard ratio 3.4, 95% confidence interval 1.4-9.9). Parallel polymerase chain reaction study of skin and blood specimens may therefore provide an initial prognostic marker that could help to monitor therapeutic strategies. A fully prospective study, with simultaneous therapeutic trials, needs to be done to confirm our findings and to include treatment variables in the statistical analysis.

EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

Little is known about genomic aberrations in peripheral T cell lymphoma, not otherwise specified (PTCL NOS). We studied 47 PTCL NOS by 250k GeneChip single nucleotide polymorphism arrays and detected genomic imbalances in 22 of the cases. Recurrent gains and losses were identified, including gains of chromosome regions 1q32-43, 2p15-16, 7, 8q24, 11q14-25, 17q11-21 and 21q11-21 (> or = 5 cases each) as well as losses of chromosome regions 1p35-36, 5q33, 6p22, 6q16, 6q21-22, 8p21-23, 9p21, 10p11-12, 10q11-22, 10q25-26, 13q14, 15q24, 16q22, 16q24, 17p11, 17p13 and Xp22 (> or = 4 cases each). Genomic imbalances affected several regions containing members of nuclear factor-kappaB signalling and genes involved in cell cycle control. Gains of 2p15-16 were confirmed in each of three cases analysed by fluorescence in situ hybridization (FISH) and were associated with breakpoints at the REL locus in two of these cases. Three additional cases with gains of the REL locus were detected by FISH among 18 further PTCL NOS. Five of 27 PTCL NOS investigated showed nuclear expression of the REL protein by immunohistochemistry, partly associated with genomic gains of the REL locus. Therefore, in a subgroup of PTCL NOS gains/rearrangements of REL and expression of REL protein may be of pathogenetic relevance.

NPM-ALK chimeric transcripts, encoded by the t(2;5), lead to an aberrant expression of ALK by CD30+ systemic lymphomas. To determine if t(2;5) is involved in cutaneous lymphoproliferative disorders, we studied 37 CD30+ cutaneous lymphoproliferations, 27 mycosis fungoides (MF), and 16 benign inflammatory disorders (BID). NPM-ALK transcripts were detected by nested reverse transcription-polymerase chain reaction (RT-PCR) in 1 of 11 lymphomatoid papulosis (LyP), 7 of 15 CD30+ primary cutaneous T-cell lymphoma (CTCL), 3 of 11 CD30+ secondary cutaneous lymphoma, 6 of 27 MF, and 1 of 16 BID. However, the expression of NPM-ALK transcripts was not associated with ALK1 immunoreactivity in MF, LyP, or BID cases. Only 1 CD30+ primary CTCL and 3 CD30+ secondary cutaneous lymphoma were ALK1 immunoreactive. The ALK1+cases were also characterized by amplification of tumor-specific genomic breakpoints on derivative chromosome 5. These cases, except for 1 secondary cutaneous lymphoma, were also characterized by reciprocal breakpoints on derivative chromosome 2, leading to the expression of reciprocal ALK-NPM transcripts. Amplification of chromosomal breakpoints on both derivative chromosomes could represent an alternative to conventional cytogenetics for the diagnosis of t(2;5) and seems to be more reliable than the detection of cryptic NPM-ALK transcripts by nested RT-PCR.